PROJECT SUMMARY Due to an ever-increasing number of cancer survivors, representing approximately 4.5% of the population in the United States (2014), second malignancies related to chemotherapy and/or radiotherapy is a significant concern in public health. However, underlying mechanisms of second malignancies are poorly understood. While it is well known ionizing radiation can induce cancers in small animal models, whether radiation causes second cancer by creating initiating mutations or by promoting the expansion of cells that harbor a pre-existing mutation remains a field of active study. This knowledge gap represents a substantial barrier to assessing the risk of second malignancies and to develop novel strategies for preventing or mitigating this clinically significant side effect of cancer therapy. The long-term goal of this research is to study how ionizing radiation alters the microenvironment and cell competition within the stem/progenitor pool to promote the development of second hematological malignancies. To successfully launch my independent research program studying this question, I will use this K99/R00 award to achieve my short-term objectives to 1) develop expertise in hematopoiesis and thymopoiesis, 2) gain knowledge and skill sets studying epigenetic changes in the onset and progression of radiation-induced thymic lymphoma, and 3) receive focused training in grant writing, leadership and career development. These three objectives represent areas where continued development is crucial for my successful transition to an independent investigator. The proposed research is innovative in that it challenges the conventional view that radiation causes cancer predominantly by creating new mutations. Instead, this proposal tests the hypothesis that radiation promotes the growth of cells with preexisting mutations. The proposed research is significant because it will provide a mechanism for non-targeted effects of radiation- induced carcinogenesis, which remains poorly understood for over 60 years. Ultimately, the conceptual advances made possible by the proposed research will enable more complete understanding of mouse models of radiation-induced thymic lymphoma and establish a preclinical platform for evaluating novel medical countermeasures against radiation-induced hematological malignancies.